One of the great accomplishments of modern chemical science has been the discovery of a multitude of chemical compounds that are biologically-active toward man or other animals, plants, or micro-organisms. A "biologically-active" material is one that acts upon an organism, or one of its parts or systems, to produce a physiological effect. Many of these materials have found utility in fostering human well-being or comfort. For example, pharmaceuticals are useful in promoting health or alleviating afflictions in man and domestic or other animals. Some of the pharmaceuticals, e.g., antibiotics, act by controlling harmful micro-organisms. Other pharmaceuticals, e.g., analgesics, act on a system of an organism to reduce pain.
Other biologically-active compounds are useful in furthering disease-free growth of plants, such as crops, ornamental plants, trees, and lawn grass. Some biologically-active compounds act against infective agents and others operate on the systems of the plant organisms to control the infective agents.
Useful biologically-active compounds are also employed to control organisms that cause harm or discomfort to humans or other animals or plants. For example, insecticides are used to eradicate disease-spreading vectors such as malaria-carrying mosquitos; herbicides are employed to control weeds on crop land; and fungicides or antioxidants are applied to foods to retard spoilage.
While these biologically-active chemicals have benefitted mankind enormously, their use has been accompanied with problems in application. For example, drugs taken orally or by injection ordinarily do not release the active ingredient evenly over time. However, it is nearly always desirable to have a constant level of a drug supplied to the body over the period of treatment. When a conventional medicinal tablet or capsule is taken, the serum drug concentration rises rapidly to a peak that is higher than the therapeutic range, i.e., the range in which the drug concentration suffices to produce the desired therapeutic effect. Concentrations above the therapeutic range can be toxic and/or can produce adverse side effects. With time, the serum drug concentration decreases into the therapeutic range, perhaps remaining at the desired level for a hour or two, eventually dropping to a level where the drug is pharmacologically ineffective. When the next dose is taken, the cycle is repeated.
To mitigate these problems, sustained-release and controlled- release technology has been the subject of considerable effort. In sustained-release techniques, the delivery of the drug is extended over a much longer period. This allows medications to be taken less often, which is more convenient for the patient, with less chance of inadvertently missing a dose. However, the problem of uneven delivery of the medication remains.
In controlled-release techniques, the rate of delivery to the body is controlled so as to be more uniform over a prolonged period. Controlled-release properties provide all the advantages of sustained-release properties, and also minimize toxic side effects.
Numerous sustained-release techniques have been developed in an attempt to control the kinetics of drug release. These techniques include coating tablets with slow-dissolving coatings, converting drugs to salts with low solubility, compressing tablets to high density, and converting medications to suspensions or emulsions. For example, in U.S. Pat. No. 3,350,270 to William E. Gaunt, sustained-release is claimed by enveloping a drug in a film of aluminum acetylsalicylate, optionally combined with a film-forming polymer.
Another system for sustained-release, widely used today, employs a capsule containing hundreds of tiny beads consisting of a core of medication coated with wax layers of varying thickness. The drug is released, depending on the depth of the coating on the individual beads, from a few minutes to 12 hours or more, to prolong the effect of the medication.
Progress also has been made in developing controlled-release technology. One approach utilizes a "reservoir", which is a drug body surrounded by a non-biodegradable polymer. Release of the drug depends on diffusion through the polymer. An example of such a reservoir is the closed silicone rubber tube containing a contraceptive drug, which has been designed to be implanted in the body. Organic cation exchange resins have also been used to provide a "reservoir" effect In U.S. Pat. No. 2,990,332, J. W. Keating discloses cationic drugs, e.g., ephedrine, complexed with sulfonic acid cation exchange resins. The medication is said to be released slowly, at an even rate, as metal cations in the gastrointestinal tract exchange with the cationic drugs in the complex.
Controlled-release can also be obtained from "matrix" devices. In these devices, the drug is dispersed in a polymeric matrix, rather than encapsulated in a polymer. Medication release is controlled by diffusion of the drug through the matrix. In a variation of this technique, a slowly-decomposable or erodible polymer is employed, and medication is released as the polymer decomposes or erodes. In addition, certain drugs can be chemically attached to polymer chains, and released by cleavage of the polymer-drug bond by hydrolysis or enzyme action.
Yet another broad area of controlled-release technology involves the use of water as a solvent to release medications. This can be done by creating osmotic pressure to expel a drug solution from a capsule, or by swelling the capsule contents to enhance diffusion.
In spite of the many developments cited, improvements in controlled-release technology are needed to simplify the products, make them more economical, and to improve their delivery properties.
Another problem in taking oral medications is that the drug can be released in the wrong internal location for optimum action. Thus, many drugs taken orally are compounded with complicated coatings to prevent absorption high in the digestive tract and to release the drug later at a more appropriate location.
Yet another difficulty with oral medications is that almost all medications have an unpleasant taste. This is ameliorated by employing coated tablets, capsules, and the like. While this improves palatability, it can also add to the cost.
Yet another problem with some oral medications, such as analgesics, is irritation to the digestive tract. Buffering of the analgesic should aid in preventing irritation. Presently, many buffered analgesic compositions are mixtures of a pain- killing drug with basic metal oxides, hydroxides, or carbonates. Some of these additives are incompatible with the drug. For example, Mg(OH).sub.2 reacts with acetylsalicylic acid, causing it to decompose and become less effective. Some buffered aspirin formulations separate the drug from the buffering additives with elaborate layered designs, requiring complicated processes to make the products.
Sustained-release and controlled-release technology is also desirable in agricultural applications for biologically-active compounds. When selective herbicides are applied to crops or lawns, control of undesirable plants is achieved by applying the herbicide onto the leaf or stem surfaces of the weed and maintaining it in place until enough herbicide has been absorbed to destroy the plant. If rain occurs shortly after application, the biologically-active compound can be washed away, hydrolyzed, or otherwise dissipated, requiring one or more additional applications.
Subsequent growth of new weeds can be prevented by applying certain herbicides to the soil to inhibit seed sprouting or kill small seedlings as they emerge. The duration of effectiveness in this case is limited by the persistence of the herbicide in the soil. Rain or soil moisture can wash away, dissolve, or hydrolyze the active ingredient.
Many of the measures previously discussed for achieving sustained-release or controlled-release of drugs have been tried for agricultural chemicals, such as herbicides. However, except for very specialized applications, the added cost is prohibitive. Coating, pelletizing, or encapsulation can be effective in prolonging herbicide action. However, in addition to the added costs, these techniques often retard the absorptive process and hamper delivery of an effective dose. Therefore, most of these techniques, by their nature, result in delayed release, followed by a release surge of the active material, and then steadily decreasing levels of active material. Therefore, frequent re- application of herbicide is often necessary.
Other applications for biologically-active compounds relate to the food industry. Frozen or refrigerated fruits, vegetables, meats, and other perishable foodstuffs become, after a period of time, less palatable by oxidation from air permeating the food package. Spoilage can be retarded by using protective packaging, for example, plastic film food storage bags fabricated from materials having low gas permeability such as vinylidene copolymers. Plastic film food storage bags are useful for prolonging storage life, but even the measurably low permeability of the storage bags allows entry of atmospheric gases which can ruin the food by discoloration or rancidity.
Chemical antioxidant compounds are useful in retarding such food spoilage. While some antioxidants can be mixed with the food, this usually is not desirable, since the taste or color can be altered. Also, there is much concern over the safety of food additives in general. One means of circumventing this problem is to incorporate an antioxidant directly into the packaging material, e.g., the plastic film. This is difficult, however, as the antioxidants most frequently used are at least partially volatilized during film fabrication processes, which usually are performed at high temperatures.
While biologically-active compounds of the type discussed above are of enormous benefit, there are impediments to their use, outlined above, which limit their application. The utilization of many of these biologically-active compounds could be improved if means were available to alter the mode and/or rate of release or delivery.
Although sundry inorganic materials have been discovered which have cation exchange capabilities, there are few with anion exchange capabilities. In U.S. Pat. No. 3,002,932, Duwell and Shepard reported a non-crystalline anion exchanger based on mixed hydrated oxides of a pair of metals (Al, Si, Ti, Zn, Zr) in which the atom percentage of the metal of lower valency is 3 to 99 times that of the higher valent metal. The higher valent cation is balanced with a bound anion.
In U.S. Pat. No. 3,879,525 Miyata and co-inventors recite a hydrated composite metal hydroxide of magnesium with Al, Fe, or Cr with a variety of inorganic anions to balance the cation of higher valency.
Lee and Bauman, in U.S. Pat. No. 4,326,961, disclose a method of removing anions from solution using mixed inorganic oxides of the formula Mg(OH).sub.2.nAl(OH).sub.3.mH.sub.2 O. The same inventors, in U.S. Pat. Nos. 4,392,979, 4,392,980, and 4,446,201 disclose crystalline aluminates of the chemical formula MgA.sub.a.sup.v Z.sub.b.sup.v.nAl(OH).sub.3.mH.sub.2 O with A and Z being hydroxide, halide, inorganic acid, or organic acid anions.
In U.S. Pat. No. 4,661,282, which patent is hereby incorporated by reference, Clark reveals a high temperature anion exchange material of the structure {M.sup.1.sub.(1-x) Q.sup.(1+1).sub.x O.sub.y (OH).sub.z }(A.sup.-1).sub.d (A.sup.-2).sub.o (A.sup.-3).sub.f (A.sup.-4).sub..nH.sub.2 O with limits on x, n, y, z, d, e, f, g, 2y+z, and d+2e+3f+4g, where M and Q are metal ions and A.sup.-1, A.sup.-2, A.sup.-3, and A.sup.-4 are exchangeable anions. Materials of this invention can be used as starting materials for producing the biologically-active compounds of the present invention.
In U.S. Pat. No. 4,769,079, which patent is hereby incorporated by reference, Clark, et. al., expand this technology to disclose compositions in which the insoluble mixed metal hydrated oxide ion exchange material is complexed with a water-soluble dye anion to form a water-insoluble pigment.
Burba and Strother, in U.S. Pat. No. 4,990,268, disclose compositions of matter, useful as components in well drilling fluids, of the chemical formula Li.sub.m D.sub.d T(OH).sub.(m+ 2d+3+na)A.sup.n.sub.a in which D is a specified divalent metal ion (including Mg); T is a trivalent metal ion (including Al); A is an anion other than OH; and there are limits on m, d, m+d, na, and (m+2d+3+na). A preferred composition is MgAl(OH).sub.4.7 Cl.sub.0.3. The latter material can be used as a starting material for producing the biologically-active compounds of the present invention.
Therefore, it is a primary objective of the present invention to provide biologically-active compounds which are simple in form and are made by simple, economical processes, as well as being compounds which also have controlled-release capabilities.
In one aspect of the invention, it is an object to provide a controlled-release oral medication which is substantially insoluble in saliva and is substantially soluble under the conditions found lower in the digestive tract, such as the acidic conditions found in the stomach, or the anion-rich conditions of the intestinal tract. It is another object of this aspect of the invention to provide an oral medication which causes reduced irritation of the digestive tract relative to many current medications. Further, it is another object of this aspect of the invention to provide an oral medication which has flavor-masking capabilities without requiring coating or encapsulation of the compound.
In yet another aspect of the invention, it is an object to provide an antioxidant to reduce the spoilage rate of foods, especially those foods stored in plastic bags at room, refrigeration, or freezing temperatures. It is another object of the present invention to provide an antioxidant which is capable of being formulated into plastic film, e.g., food storage bag films, and which is substantially non-volatile at hot-film fabrication temperatures.
In another aspect of the invention, it is an object to provide a herbicide which is substantially insoluble in water and resistant to rain, so that there is less need for reapplication after unfavorable weather.
It is still another object of this aspect of the invention to provide a herbicide with controlled-release capability to exterminate weeds and provide a residual activity to prevent later germination or growth of weeds.
In other aspects of the invention, the objects are to provide biologically-active compositions containing the biologically-active compounds and methods for preparing the biologically-active compounds.